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Christhor said:
I'm going to go with the final boss from Drake's Fortune. That whole segment on the boat was amazing, with the rain. It was such a change of scenery and it was so cool. I haven't played it in years, but this part REALLY wow-ed me back in the day. They never did the bosses this well ever again.

That is your opinion but the final Boss in Drake's Fortune was quite frustrating, the Uncharted games aren't memorable for Boss battles.